Design, Synthesis and Biological Evaluation of Prodrugs of 666-15 as Inhibitors of CREB-Mediated Gene Transcription.

cAMP-response element binding protein (CREB) is a transcription factor involved in multiple cancers. Chemical inhibitors of CREB represent potential anticancer agents. We previously identified as a potent CREB inhibitor. While showed efficacious anticancer activity in vivo through intraperitoneal (IP) injection, its oral bioavailability is limited. To increase its oral bioavailability, we describe synthesis and evaluation of prodrugs based on . The amino acid esters were attempted, but they were not stable for detailed characterization. The corresponding sulfate and phosphates were prepared. The sulfate of was too stable to release while the phosphates were converted into with half-lives of ∼2 h. Phosphate was also a potent CREB inhibitor with anti-breast cancer activity. Furthermore, compound showed much improved oral bioavailability at 38%. These studies support that can be used as an oral CREB inhibitor while IP administration of is preferred for in vivo applications.